2-25161587-CGCCGCTGCT-CGCCGCTGCTGCCGCTGCTGCCGCTGCT
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BS1_Supporting
The NM_000939.4(POMC):c.280_297dupAGCAGCGGCAGCAGCGGC(p.Gly99_Ala100insSerSerGlySerSerGly) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00041 in 1,557,926 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00089 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00036 ( 1 hom. )
Consequence
POMC
NM_000939.4 conservative_inframe_insertion
NM_000939.4 conservative_inframe_insertion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.649
Genes affected
POMC (HGNC:9201): (proopiomelanocortin) This gene encodes a preproprotein that undergoes extensive, tissue-specific, post-translational processing via cleavage by subtilisin-like enzymes known as prohormone convertases. There are eight potential cleavage sites within the preproprotein and, depending on tissue type and the available convertases, processing may yield as many as ten biologically active peptides involved in diverse cellular functions. The encoded protein is synthesized mainly in corticotroph cells of the anterior pituitary where four cleavage sites are used; adrenocorticotrophin, essential for normal steroidogenesis and the maintenance of normal adrenal weight, and lipotropin beta are the major end products. In other tissues, including the hypothalamus, placenta, and epithelium, all cleavage sites may be used, giving rise to peptides with roles in pain and energy homeostasis, melanocyte stimulation, and immune modulation. These include several distinct melanotropins, lipotropins, and endorphins that are contained within the adrenocorticotrophin and beta-lipotropin peptides. The antimicrobial melanotropin alpha peptide exhibits antibacterial and antifungal activity. Mutations in this gene have been associated with early onset obesity, adrenal insufficiency, and red hair pigmentation. Alternatively spliced transcript variants encoding the same protein have been described. [provided by RefSeq, Jan 2016]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000889 (135/151892) while in subpopulation AMR AF= 0.00164 (25/15282). AF 95% confidence interval is 0.00114. There are 0 homozygotes in gnomad4. There are 58 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| POMC | NM_000939.4 | c.280_297dupAGCAGCGGCAGCAGCGGC | p.Gly99_Ala100insSerSerGlySerSerGly | conservative_inframe_insertion | 3/3 | ENST00000395826.7 | NP_000930.1 | |
| POMC | NM_001035256.3 | c.280_297dupAGCAGCGGCAGCAGCGGC | p.Gly99_Ala100insSerSerGlySerSerGly | conservative_inframe_insertion | 4/4 | NP_001030333.1 | ||
| POMC | NM_001319204.2 | c.280_297dupAGCAGCGGCAGCAGCGGC | p.Gly99_Ala100insSerSerGlySerSerGly | conservative_inframe_insertion | 4/4 | NP_001306133.1 | ||
| POMC | NM_001319205.2 | c.280_297dupAGCAGCGGCAGCAGCGGC | p.Gly99_Ala100insSerSerGlySerSerGly | conservative_inframe_insertion | 3/3 | NP_001306134.1 |
Ensembl
Frequencies
GnomAD3 genomes 0.000889 AC: 135AN: 151776Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000422 AC: 65AN: 153946Hom.: 0 AF XY: 0.000395 AC XY: 33AN XY: 83598
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GnomAD4 exome AF: 0.000358 AC: 504AN: 1406034Hom.: 1 Cov.: 33 AF XY: 0.000380 AC XY: 264AN XY: 694674
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GnomAD4 genome 0.000889 AC: 135AN: 151892Hom.: 0 Cov.: 31 AF XY: 0.000781 AC XY: 58AN XY: 74264
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:3
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 17, 2022 | This variant, c.280_297dup, results in the insertion of 6 amino acid(s) of the POMC protein (p.Ser94_Gly99dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs10654394, gnomAD 0.1%), including at least one homozygous and/or hemizygous individual. This variant has been observed in individual(s) with extreme obesity but a second variant was not observed (PMID: 9768693). This variant is also known as the 18bp insertion between codon 73 and 74. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 04, 2017 | - - |
| Uncertain significance, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Obesity due to pro-opiomelanocortin deficiency;C4054476:Inherited obesity Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | Feb 18, 2022 | - - |
Inherited obesity Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 25, 2024 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at